Intrathecal Tetanus Immunoglobulin to Treat Tetanus (ITITTT)

Intrathecal Immunoglobulin for Treatment of Adult Patients With Tetanus: a Randomized Controlled 2x2 Factorial Trial

To establish whether the addition of intrathecal tetanus antitoxin reduces the need for mechanical ventilation in patients with tetanus

The investigators will conduct a randomised partially-blinded controlled 2x2 factorial trial. First, adults admitted to the Intensive Care Unit at the Hospital for Tropical Diseases Ho Chi Minh City will be randomized to receive either human (3000 IU) or equine (21,000 units) intramuscular antitoxin. Second, participants will be randomized to receive either standard treatment with intramuscular antitoxin alone or with the addition of 500 IU intrathecal human antitoxin. Patients with prior antitoxin treatment and those with contra-indications to lumbar puncture or antitoxin treatment will be excluded. All patients will receive other standard tetanus treatment as deemed necessary by the attending physicians. Spasms will be treated with benzodiazepines as first-line therapy. Patients with spasms not controlled with benzodiazepines will receive tracheostomy, paralysis, magnesium sulphate and mechanical ventilation. Heart rate, BP, temperature and daily drug use will be recorded throughout the ICU stay. Patients will be followed following discharge from hospital until 240 days for disability/ death.

Human tetanus immunoglobulin (Tetagam-P): Injection (prefilled syringe) 250 IU in 1 ml - Intrathecal 500 IU

Human tetanus immunoglobulin (Tetagam-P): Injection (prefilled syringe) 250 IU in 1 ml - Intramuscular 3000 IU OR Equine antiserum - 21,000 units

Adults admitted to ICU at Hospital for Tropical Diseases will be randomized to receive either human (3000 IU) or equine (21,000 units) intramuscular antitoxin. Second, participants will be randomized to receive the addition of 500 IU intrathecal human antitoxin.

First, adults admitted to ICU at Hospital for Tropical Diseases will be randomized to receive either human (3000 IU) or equine (21,000 units) intramuscular antitoxin including a 0.05ml test dose (ie 75 units equine antitoxin or 12.5 IU human antitoxin). Second, participants will be randomized with sham procedure

Criteria for mechanical ventilation are oxygen saturation (SpO2) <90%; or partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) <250; or excessive spasms necessitating muscle paralysis. These criteria are intended as a guide and the final decision to ventilate a patient rests with the individual doctor responsible for the patient.

New antibiotic prescription during ICU stay (excluding antibiotics for tetanus or initial entry site infection)

Definition of Ventilator associated pneumonia (VAP): Mechanical ventilation for at least 48 hours and with the tube in place within the last 48 hours and 2 of: Temperature > 38°C or < 36°C White blood cell count <4.0 x 109/L or ≥12 x 109/L Purulent respiratory secretions New or progressive changes on chest radiography (for VAP) Plus for microbiologically confirmed VAP Bacterial growth of ≥105 cfu/ml from endotracheal aspirate (ETA) (or ≥104 cfu/ml from Broncho Alveolar Lavage (BAL))

At least 3 of the following criteria: Tachycardia Heart Rate (HR)> 100 bpm Hypertension Systolic Blood Pressure (SBP) > 140 mmHg Hypotension Mean Arterial Pressure (MAP) < 60 mmHg Pyrexia > 38°C Alteration between hypertension and hypotension

Inclusion Criteria: All adult patients (≥16 years old) with a clinical diagnosis of generalized tetanus admitted to the intensive care unit (ICU) at the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam Exclusion Criteria: Prior administration of antitoxin during this episode Contra-indication to use of human or equine antitoxin Contra-indication to lumbar puncture Already receiving mechanical ventilation or expected to require this before intrathecal injection can be given Pregnancy Informed consent not obtained

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